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Autism is a very heterogeneous disorder. As the grand lady of neurology, Dr. Isabelle Rapin liked to emphasize when training new students “If you have seen one child with autism, you have seen one child with autism.” This heterogeneity has made understanding causes and designing effective treatments more challenging than it would be otherwise.

However, a new study published this week in Nature and supported by Autism Speaks’ Autism Tissue Program and Autism Genome Project reveals that the heterogeneity may not be as problematic as it initially seems. Differences in common molecular pathways appear to underlie the pathology in the brains of individuals with ASD.

Daniel Geschwind, M.D., Ph.D. (UCLA) launched an ambitious study to examine not just the variants of genes that may confer risk for autism, but the interaction with those genes and proteins working to support brain function. Looking for patterns of interaction in the brain, Dr. Geschwind and his colleagues sought to characterize the transcriptome – the set of fragments of instructions, called RNA, read from the gene DNA on the path to making functional proteins. Importantly, unlike the gene DNA that is relatively fixed for an individual’s life, the RNA transcriptome is modified through experience and interaction with the environment.

The authors analyzed patterns of expression of RNA for three areas of the post-mortem brain tissue from individuals with ASD or typically-developing individuals. Two areas of the late-developing cerebral cortex (prefrontal cortex and the superior temporal gyrus) and a region of the cerbellum known as the vermis were compared between the autism and typically developed brain tissue. The first big surprise was that although the cortex transcriptome revealed over 400 different genes with different expression between the autism and typical brain tissue samples, the similar comparison in the cerebellar transcriptome revealed exactly two differently expressed genes. Whatever differences exist in the brains of individuals with autism, these differences are greatest in the instructions that guide the structure and function of the cerebral cortex.

This, however, was just the beginning of what the research team found. Imagine the cerebral cortex of brain is like a bustling metropolis – one part of the city develops into a residential area and the other becomes a business district. Both neighborhoods have very distinctive features that make them unique due in part to the time and manner in which they developed and the people who inhabit them. So too for different regions of the typically-developing cerebral cortex. Different regions of the cortex develop at different times and with different inputs from the environment. The prefrontal cortex is one of the late-developing regions in the infant brain. Different regions also serve different functions, like integrating information from sight, sound and touch in the case of the superior temporal gyrus, and higher cognitive functions in the prefrontal cortex.

Importantly for Dr. Geschwind and his colleagues, these two cortical regions also have their own unique pattern of expression in brains from typically developed individuals. However, when looking for these unique signatures, the research team instead found surprisingly similar patterns of gene expression across the two regions in the brains of people with autism. Referring back to the metropolis analogy, in the autism brain samples, the residential and business districts are more alike than they ought to be.

There were also differences in expression of two gene networks between the autism and control brain samples. The first network of genes encodes synaptic function. This is reassuring because most of the autism risk genes identified through previous studies focused on synaptic function. The second network of differential gene expression was related to immune function and inflammation. This too harkens back to previous studies showing inflammation and immune system activation in the brains of individuals with autism. This gene network does not correlate with the results of large gene association studies like the synaptic network, indicating that secondary or environmental effects are involved in stimulating the observed inflammatory markers.

“This is the first study to show differences in the patterns of gene expression between brain regions, said Rob Ring, Ph.D., Autism Speaks vice president for translational research. “It’s those patterns of gene expression that enable the brain to function normally and to communicate properly with other regions of the brain.”

Taken together, these results have quite an impact on how we understand autism. The similarity of gene expression across different regions of cerebral cortex in the brains of individuals with autism tells us that we should look closely at very early brain development as these patterns in cerebral cortex emerge. The same goes for the network of synaptic genes that are differentially regulated in individuals with autism. However, the differences observed in immune and inflammation gene networks are more likely to be related to secondary or environmental effects. We must follow all the leads this research has provided if we are to make the next steps in developing supportive treatments and therapies for those living with autism spectrum disorders today.

In honor of World Autism Awareness Day, the Interagency Autism Coordinating Committee (IACC) has released its Summary of Advances for 2010. Twenty articles that were published in 2010 were selected across each of the five areas of focus on the IACC strategic plan. Autism Speaks’ Chief Science Officer, Geri Dawson, Ph.D., is a member of the committee and was pleased to see advances across the range of autism research and said, “It is encouraging to see the diversity of scientific advances that were made in 2010.“ Dawson noted, “studies that were deemed especially noteworthy included environmental research, genetic discoveries, new early intervention approaches, and assessment of medical conditions such as GI problems and mitochondrial dysfunction.”

The list of advances comes at a time of celebration and reminds us of how much has happened in 2010, yet we are well aware of how far we need to go. Dawson remarked, ”While it is encouraging to see the advances made in 2010, it is important that we continue to advocate for increased federal funding for autism research. This is a step in the right direction but important issues remain to be addressed regarding the causes of autism and, more importantly, more effective ways of treating autism throughout the lifespan.”

Science moves so slowly and is so labor-intensive that we don’t often have moments to celebrate an achievement or breakthrough that has resulted from our investments. With this week’s announcement of Phase 2 results from the Autism Genome Project, we are celebrating such an achievement.

Several years ago, when I was a professor at the University of Washington, I remember a phone call from Andy Shih, Ph.D. (Autism Speaks VP, Scientific Affairs) who asked if he could take my colleague, Jerry Schellenberg, and me out to breakfast. Over coffee, Andy described to us an idea he had: Would we be willing to collaborate with other scientists around the world and add the genetic data we have been collecting to a combined database? While each of us at that time had been working independently to try to discover autism risk genes, we knew that ultimately we would need much larger samples to deal with the significant heterogeneity that exists in autism spectrum disorder. After a lot of discussion and questions, Andy convinced us that this would be a worthwhile effort and thus we became part of what became known as the “Autism Genome Project,” or the AGP. Eventually, Andy talked with over 50 groups worldwide and cajoled each of them to join the effort. What ensued was a series of monthly conference calls, complex negotiations and agreements that Andy helped broker, the creation of a combined database, and yearly meetings during which the goals for analysis and future data collection would be discussed. Today, the AGP is considered a driving force in autism genetic research.

Meanwhile, Clara Lajonchere, Ph.D. (Autism Speaks VP, Clinical Programs) was spearheading an effort to create a database of multiplex families called the Autism Genetic Resource Exchange (AGRE). She was leaving most of us collecting similar samples in the dust as she quickly assembled the largest private genetic individual data base that exists. Her ability to form partnerships with families, engaging them in the process of scientific discovery, was a model for us all. Not surprisingly, Clara readily agreed to join the AGP since AGRE’s basic premise was “collaboration and data sharing.”

Fast forward to this week when the AGP published the largest and most comprehensive study of copy number variations (CNV) – small deletions or duplications in our genome that can disrupt gene function – in autism families. By comparing CNVs found in 1,000 individuals with autism with those from 1,300 individuals without autism, the AGP reported the following:

Several novel ASD genes were discovered, and many genes previously implicated by other studies were confirmed. Some of these genes are involved with communication between neurons, while others help regulate cell growth and how they respond to environmental stimuli.

It was confirmed that autism risk genes are rare variants in our genome that occur very infrequently or not at all in the general population, and each person with ASD may have a unique risk gene or set of risk genes. Some of these genes are “highly penetrant” meaning that, if you carry this risk gene, you very likely will develop ASD, whereas other only raise the risk for ASD and need to combine with other genetic and/or environmental risk factors to cause ASD. Some of these are inherited, but many appear “de novo” meaning that they only exist in the child and not the parents.

In the not-so-distant future, we will start to see more comprehensive genetic testing being conducted in the clinic to provide parents with information about whether their child may be at risk for ASD, so they can watch for signs or better understand the cause of their child’s ASD. It will be important to consider carefully what tests are appropriate and interpret them in a manner that is responsible and helpful for parents.

Although the fact that so many rare genes can be related to risk for autism seems to form an overwhelmingly complex picture of autism, there is a path forward: These genes appear to cluster around specific biochemical pathways in the brain and, thus, point to new directions for developing drugs that could potentially help recover function of these pathways. This is good news for families.

Most of all, I see the publication of this report as a celebration of the fruitful partnership between the families and the scientific community. While Autism Speaks staff like Andy and Clara helped create and implement unique and productive scientific endeavors like the AGP, ultimately, it is the families who contributed their time and literally a part of themselves that is helping us put together this puzzle called autism piece by piece.

Genetic research is one of the exciting avenues of investigation that was highlighted at this year’s IMFAR meeting. The section on human genetics started with a description of the largest study of autism twins to date. This study, described by Dr. Joachim Hallmayer, has concluded the data collection phase and is beginning to shed new light on how much autism can be explained by genes and how much by environment. Because identical twins share 100% of their DNA while fraternal twins share only approximately 50%, geneticists can compare the relative contribution of genes and environment, since it is assumed that for each twin pair, the environment is the same. Clearly, both environment and genes are involved but this study may help to identify to what extent.

Dr. David Ledbetter described his effort to gather anonymous genetic information on chromosomal microarays from hundreds of thousands of patients with autism spectrum disorder and developmental delay. He is doing this by forming partnerships with over 120 clinical labs throughout the U.S. Dr. Ledbetter, a world-reknown expert in cytogenetics, has the knowledge and respect of the scientific community to achieve the goal of creating data standards and pooling information to show which chromosomal changes are most often identified in these groups. Deletions in regions on chromosomes 16 and 22 are identified consistently. Although still rare, an understanding of altered genes in these regions may lead us to identify new subtypes of autism.

Other talks focused on studies of brain and face development (since these happen at the same time) in families with autism from the Autism Genetic Resource Exchange, an update from the Autism Genome Project, and a fascinating talk from Sun-Chiao Chang (working with Dr. Susan Santangelo) on sex-specific effects in autism spectrum disorder. Ms. Chang identified several genes which seem to have an effect only in males, possibly helping to explain the common finding that there are four times as many males with autism as there females.

In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our 19th item, First Successful Autism Genome-Wide Association Study Results, is from Autism Speaks’ Top 10 Autism Research Events of 2009.

Advances in technology and analytical methods over the past several years have enabled a better understanding of genetic risk factors for ASD. The human genome has over 6 billion DNA nucleotides. Until recently, it has been extremely difficult for scientists to compare two groups of individuals – one affected by a condition versus a comparison group – in terms of their detailed DNA because such comparisons require the analysis of at least half a million to a million individual locations in the genome of thousands of people. New methods, called Genome-Wide Association Studies (GWAS), have now made it possible to perform such comparisons and identify single changes in DNA nucleotides as specific genetic risk factors. Although this powerful technology has already produced exciting findings in other complex diseases, it wasn’t until 2009 that GWAS studies finally began to bear fruit for autism. In the Spring and again in the Fall, researchers reported successful application of GWAS technology to ASD.

GWAS is a powerful analysis technique that allows researchers to sift through hundreds of million of bits of genetic data to identify changes to the genetic code that are associated with a disease. Because the approach is not based on any specific biological hypothesis, scientists can cast the broadest experimental net possible, and use sophisticated statistical methods to establish the disease association. In recent years, GWAS has been successful in identifying susceptibility genes for such diverse conditions as macular degeneration, diabetes, rheumatoid arthritis, Crohn’s disease, and bipolar disorder. In April 2009, a large team of scientists led by investigators at Children’s Hospital of Philadelphia, reported results from the first successful GWAS study in autism. Tens of thousands of DNA samples are required for GWAS to produce meaningful results, so working with collaborators that included members of the Autism Genome Project, the researchers pooled samples from the Autism Speaks-funded Autism Genetic Resource Exchange (AGRE) combined with many other collections. The result was identification of a DNA variant associated with the genes cadherin 10 and 9, which are responsible for creating molecules that facilitate the formation of neural connectivity. This finding is consistent with accumulating evidence suggesting abnormal interactions between neurons may be at the core of the deficits seen in autism.

The idea that faulty connections between neurons plays a major role in ASD was further supported with the publication of the second autism GWAS study in October. Also working with AGRE and members of the Autism Speaks-funded Autism Genome Project, a collaboration led by investigators from Boston’s Autism Consortium and Johns Hopkins University used a very different statistical approach to discover an association between ASD and the gene semaphorin-5A. Similar to the cadherins identified in the first study, semaphorin 5A is thought to play an important role in neural development.

Taken together, these two groundbreaking studies confirm the potential for GWAS to make successful contributions to our understanding of autism genetics. Remarkably, out of the approximately 20,000 different human genes the experiments could have identified, the genetic variations that were uncovered are genes involved in brain development, serving to expand and reinforce our current thinking about biological mechanisms of autism. Like all new findings, they continue to focus the attention of the scientific community on the next directions for research and exploration.

Update since this story was published: DNA technology has once again advanced dramatically. New high-throughput techniques have finally made it possible to sequence entire stretches of genes, known as exons, in large numbers of patients. At the end of 2009, stimulus funds from the American Recovery and Reinvestment Act were awarded to investigators from the Autism Genome Project and the Autism Consortium who will use these new techniques to conduct a very detailed examination of 1,000 different genes linked to autism using several thousands of families who have kindly provided their DNA.

In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our 13th item, AGP Releases First Results, is from Autism Speaks’ Top 10 Autism Research Events of 2007.

Launched in 2004 by Autism Speaks, the Autism Genome Project, or AGP, is the largest study ever conducted to find the genes associated with risk for developing autism. Comprised of approximately 50 academic and research institutions representing 19 countries, many of the world’s leading genetics researchers pooled their resources and used a promising new technology, the DNA microarray, to scan the human genome in search of the genetic causes of this devastating disorder. In 2007, the first of several planned analyses was made public.

The first phase of the project, a research partnership with the National Institutes of Health, consisted of two scans of the human genome searching for regions that may harbor autism susceptibility genes. The scans analyzed DNA samples from nearly 1,200 families and in February the preliminary results were reported in the leading international journal Nature Genetics. The AGRE collection made up almost one third of the samples for this study. Highlights include the identification of a novel region on chromosome 11, additional support for previously identified regions on chromosome 2 and 7, linkage signals that appear to be present only in affected girls, and the identification of a specific candidate gene, neurexin, associated with copy number variations (CNV).

Completion of the first phase of AGP showed the world that scientists could work together to tackle the complexities of autism. Autism Speaks was a leading voice in the formation of AGP, as it believes that breakthroughs will happen faster if researchers unite in their efforts. Given the heterogeneity in underlying risk factors in autism, expansion of consortia such as AGP will absolutely be required.

Did you know?: In order to form the Autism Genome Project, Autism Speaks brought together 170 of the world’s leading geneticists. With over 3,500 families in its dataset, the AGP is the largest collaboration in the world to study the genetics of autism. By using state-of-the-art technologies and combining their results across sites, AGP and its members have been involved with every major autism genetic discovery reported over the past two years. With more major findings expected from the consortium in the near future, the AGP is now widely recognized as major force in the field of autism genetics.